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Development of a Safe and Effective Pediatric Dosing Regimen for Sotalol Based on Population Pharmacokinetics and Pharmacodynamics in Children With Supraventricular Tachycardia

Stephanie Läer, MD, PhD^_*,_*, Jan-Peer Elshoff, PhD^_*, Bernd Meibohm, PhD, FCP, Jochen Weil, MD, PhD, Thomas S. Mir, MD, Wenhui Zhang, PhD and Martin Hulpke-Wette, MD

^_* Department of Clinical Pharmacy and Therapeutics, University Düsseldorf, Düsseldorf, Germany
University of Tennessee Health Science Center, Department of Pharmaceutical Sciences, Memphis, Tennessee
Department of Pediatric Cardiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
Department of Pediatric Cardiology, University of Göttingen, Göttingen, Germany

View larger version (16K): [in a new window]   Figure 1 Probability of arrhythmia suppression in the 15 children with supraventricular tachycardia (COES study patients) versus sotalol trough concentration under steady-state conditions and an 8-h dosing interval. Filled circles = 6 neonates (<28 days).

View larger version (23K): [in a new window]   Figure 2 (A) QT-RR (open circles) intervals of patients under sotalol (1 to 9.9 mg/kg/day) therapy. Filled circles = a 50-day-old infant (4.1 mg/kg/day); large filled circles = 8-year-old child (2.9 mg/kg/day). Solid line = fit of baseline neonate/infant QT-RR data dotted line: a fit of baseline children/adolescent data. (B) Differences of QTcPOP intervals from baseline in neonates (filled circles) and all other pediatric patients (open circles) versus sotalol concentration. (C) Sensitivity of the QTc interval prolongation towards sotalol (dQTcPOP).

View larger version (22K): [in a new window]   Figure 3 Mean ± SD QT interval prolongation normalized for sotalol concentrations. (A) dQTcPOP; (B) dQTcF; (C) dQTcB in neonates (<28 days), infants (<2 years), and children and adolescents (<15 years). p values according to ANOVA with Tukey's honestly significant difference test (#) and least significance difference test (°).

View larger version (18K): [in a new window]   Figure 4 Measured (closed diamonds) and model predicted oral sotalol clearance based on body weight (open diamonds). Median (solid line) and the 10th and 90th percentile (dashed line) of 1,000 simulated data sets.

View larger version (55K): [in a new window]   Figure 5 Black box plots and hatched bars indicate recommended dosing range. (A) Simulated sotalol trough concentrations (125 patients per group and dose level) for pediatric patients with supraventricular tachycardia. Lines indicate 50% and more than 95% efficacy. (B) Patient fraction with 50% and more than 95% probability of arrhythmia suppression. Arrows indicate start and target doses.